Manufacture of piperitenone

ABSTRACT

Manufacture of piperitenone by mixing excess mesityl oxide with 10 to 70% by weight aqueous potassium hydroxide solution, heating the mixture to a temperature of between 20*C and the boiling point and introducing the methyl vinyl ketone into the heated mixture. d,1-Menthol is obtained directly, or via a mixture of menthone and isomenthone, from the piperitenone which is obtained in good yield.

United States Pat ent [191 Pasedach et al.

-' 11 1 3,870,761 [451 Mar. 11, 1975 MANUFACTURE OF PIPERITENONE [75] Inventors: Heinrich Pasedach, Ludwigshafen;

Albrecht Friederang, Mannheim both of Germany [22] Filed: July 17, 1972 [2]] Appl. No.: 272,147

[30] Foreign Application Priority Data July 23, I971 Germany 2136885 Jan. 27, 1972 Germany 2203807 [52] US. Cl. 260/586 C, 260/631 H [51] Int. Cl... C07c 49/48, C070 45/00, C07C 29/00 I58] Field of Search 260/587, 631.5, 586 C, 260/631 H [56] References Cited UNITED STATES PATENTS 3.238.261 3/1966 Beerboom 260/587 OTHER PUBLICATIONS Ueda; Hiroo, Bull Agr. Chem. Soc," Vol. 64, pp.

Moller, Chemistry of Org. Comp. 3rd Ed. p. 958. (1965).

Primary Examiner-Leon Zitver Assistant Etuminen-Norman Morgenstern Attorney, Agent, or Firm-Johnston, Keil, Thompson & Shurtleff 57 ABSTRACT Manufacture of piperitenone by mixing excess mesityl oxide with 10 to 70% by weight aqueous potassium hydroxide solutiomheating the mixture to a temperature of between 20C and the boiling point and introducing the methyl vinyl ketone into the heated mixture. d,1-Menthol is obtained directly, or via a mixture of menthone and isomenthone, from the piperitenone which is obtained in good yield.

6 Claims, No Drawings MANUFACTURE OF PIPERITENONE The invention relates to an improved process for the manufacture of piperitenone by reaction of methyl vinyl ketone with excess mesityl oxide in the presence of basic catalysts.

It is known to manufacture piperitenone by reaction of mesityl oxide with methyl vinyl ketone in the presence of basic condensing agents.

Thus Bergmann Bergman et al., (J. Org. Chem., 24, 994 (1959)) describe a process in which sodium tamylate is used as a basic condensing agent and toluene as the solvent and p'iperitenone is alleged to be obtained in a yield of 41% of theory. Later investigations by Naves et al., (Bull. Soc. Chim. France, 1960, 378 and Compt. rend., 251, 1 130 (1960)) however showed that the process of Bergmann et al., mainly yields isoxylitone and only less than 8% of piperitenone.

Furthermore, J. J. Beereboom (US. Pat. No. 3,238,261 and J. Org. Chem., 31, 2026 (1966)) describes the reaction of methyl vinyl ketone with excess mesityl oxide in the presence of potassium hydroxide powder in tetrahydrofuran as the solvent. The piperitenone obtained is purified in a very expensive manner via the piperitenone bisulfite adduct. In this process, yields of piperitenone of between 36 and 54% of theory obtained.

A similar process is described by S. Ohshiro et al., (Yakugaku Zasshi, 88, 417 (1968)). Here again the reaction of methyl vinyl ketone with excess mesityl oxide takes place in the presence of potassium hydroxide powder but without addition of tetrahydrofuran as the solvent. The piperitenone obtained is converted into a mixture of menthone and isomenthone by catalytic hydrogenation. However, in this process the yields of piperitenone are again only about 53%; furthermore, using this process the menthone/isomenthone mixture is obtained in only 64.6% yield and in a purity of only 89.8%. For this reason, the further reaction to give pure menthol has to be carried out in an involved manner via menthoneoxime (Jap. Patent 7,009,375) and mentylamine, which makes it doubtful whether the process is suitable for commercial operation.

It is an object of the invention to provide a process which enables piperitenone, and hence the mixture of menthone and isomenthone which can be manufactured therefrom by reduction, to be obtained in a simple manner, in better yields and higher purity.

We have found that the process for the manufacture of piperitenone by reaction of methyl vinyl ketone with mesityl oxide in the presence of a basic catalyst, in which methyl vinyl ketone is slowly introduced into excess mesityl oxide, may be carried out particularly advantageously by mixing excess mesityl oxide with 10 to 70% w/w aqueous potassium hydroxide solution, heating the mixture to a temperature of between C and the reflux temperature (approx. 100C), preferably between 50C and the reflux temperature, and introducing the methyl vinyl ketone into the heated mixture.

According to a particularly simple embodiment of the invention, crude methyl vinyl ketone, as is obtained from 3-keto-1-butanol in known manner by splitting off water with acid, for example oxalic acid, is used. Instead of pure 3-keto-1-butanol it is possible to use, for example, the crude product from the thermal condensation of acetone with formaldehyde (see German Patent 1,277,235), that is to say, a keto-butanol which contains impurities and major amounts of water. If, for

example, 50 percent strength aqueous keto-butanol is heated to the boil with oxalic acid, a methyl vinyl ketone/water azeotrope is continuously distilled off and 7 fresh 50 percent keto-butanol is added, an 80 to 85 per bent strength aqueous methyl vinyl ketone is obtained which can be used directly for the reaction according to the invention. In that case, admittedly, it is necessary to ensure that in the reaction with mesityl oxide the amount of water introduced with the methyl vinyl ketone is removed from the system by distillation.

It is surprising that thereaction of methyl vinyl ketone with excess mesityl oxide in the presence of aqueous potassium hydroxide solution and using methyl vinyl ketone/water mixtures should take place with far higher yields than could be expected from the known processes, especially since Beereboom in US. Pat. No. 3,238,261 states that better yields are obtained if the tetrahydrofuran used as the solvent is dried before the reaction, which means that the presence of water in the reaction mixture was regarded to be disadvantageous.

Usually, mesityl oxide condenses in the presence of bases to give isoxylitones (Furth and Wiemann, Bull. Soc. Chim. Fr., 1965, 1819), a reaction which takes place particularly readily at elevated temperature. It was not to be foreseen that this undesired side-reaction would be strongly repressed by the presence of water whilst the condensation of the mesityl oxide with methyl vinyl ketone to give piperitenone is favorably influenced.

The amount and concentration of the potassium hydroxide solution used and the reaction temperature can be varied within wide limits but in order to achieve particularly good yields it proves necessary to use more dilute solutions at high temperatures and more concentrated solutions at lower temperatures. For example, a concentration of 40 to 60% is advantageously used at a temperature of 50 C. A particularly important feature for commercial operation is that the reaction can also be carried out at the reflux temperature (approx. C). At temperatures of between about 80C and the relux temperature the aqueous potassium hydroxide solution is advantageously used in a concentration of 20 to 40%, preferably of 25 to 35%.

The potassium hydroxide is generally used in amounts of 0.05 mole to 1.5 mole, preferably of 0.1 mole to 0.7 mole, per mole of methyl vinyl ketone; if larger amounts of alkali are used, there is increased formation of by-products.

Instead of potassium hydroxide solution, aqueous sodium hydroxide solution can be used (compare example 17); the yields are however much lower and more by-products result.

At one and the same temperature, more undesired by-products are formed when using more concentrated alkalis whilst when using more dilute alkalis the yield diminishes A further advantageous embodiment of the present process consists in after-treating the crude piperitenone, preferably after neutralization and distillation with potassium hydroxide solution, for approx. half to 30 hours at about 20 to 80C, preferably 40 to 50C. 1f the crude piperitenone is after-treated as a distillate, potassium hydroxide powder is conveniently used. lt is, however, also possible, as in the after-treatment of the reaction product which has not been distilled, to employ an aqueous potassium hydroxide solution of approx. 20 to 60 percent strength. This results in a further increase in yield to above 80% of theory.

Mesityl oxide is used in an excess of 5 to moles, preferably of about 10 moles, per mole of methyl vinyl ketone and serves as the sole solvent.

To carry out the process, the reactive methyl vinyl ketone is slowly added to the heated mixture of excess mesityl oxide and the alkali solution in a period of, generally, 10 minutes to several hours, preferably to 60 minutes. If the reaction is carried out at relatively low temperature it is advisable to keep the reaction batch, after completion of the addition of the methyl vinyl ketone, for some time longer, that is to say up to approx. 30 hours, at the reaction temperature. If, on the other hand, the reaction is carried out at a higher temperature, especially at the reflux temperature, only a relatively short after-treatment is necessary.

Because of the known tendency of mesityl oxide to form isoxylitones under the action of alkali and because of the reactivity of the methyl vinyl ketone it appeared desirable to carry out the reaction at a low temperature, especially since it is stated in US. Pat. No. 3,238,261 that temperatures of above 30C offer no advantages and frequently lead to reduced yields of piperitenone. It was therefore surprising that higher yields of piperitenone are obtained if, in accordance with the invention, the entire reaction is carried out at an elevated temperature, especially at the reflux temperature, that is to say if the method of the known processes of first bringing the methyl vinyl ketone into contact with the mesityl oxide and the alkali catalyst whilst cooling intensely and only then raising the temperature, which makes commercial operation of the process difficult, is not followed.

The correct balancing of the alkali concentration and the reaction temperature is of decisive importance as regards the yield of piperitenone and its purity. Most expediently, the process is carried out at the reflux temperature and with a 25 to potassium hydroxide solution. When using commercially available strength potassium hydroxide solution, the optimum reaction temperature is to C; even at a reaction temperature of C the proportion of by-products is appreciably higher whilst at 50C the yields obtained are less.

After completion of the reaction, the reaction mixture is neutralized with an inorganic or organic acid, preferably with formic acid, acetic acid or oxalic acid, and the organic phase is distilled. The excess mesityl oxide is thereby recovered in a simple manner.

The yield of crude piperitenone depends on the quality of the mesityl oxide employed. Since mesityl oxide is used in large excess, a possible water content of the mesityl oxide can have an effect on the concentration of the alkali hydroxide solution and hence on the yield of piperitenone. In such cases it is advisable to use a more concentrated aqueous solution so that the concentration of the solution present during the reaction lies within the abovementioned limits.

Using the process according to the invention, yields of 68 to 82% of piperitenone are obtained with technical mesityl oxide.

The crude piperitenone obtained is very difficult to purify by fractional distillation. It is much easier to remove the by-products if the crude piperitenone is hydrogenated to give a mixture of menthone and isomenthone and this mixture is subjected to fractional distillation. The reduction takes place in accordance with customary methods, for example by hydrogenation with palladium/active charcoal as the catalyst.

The present process for the manufacture of a menthone-isomenthone mixture offers substantial advantages over the known processes. The yield of piperitenone is 68 to 82% as compared to 53 or 54% in the known processes. Technical aqueous potassium hydroxide solution can be used as the condensing agent. Furthermore, an expensive solvent is not required; the excess mesityl oxide can be recovered simply and, as is shown by the examples, the process is extremely simple to carry out. On distilling the product obtained using potassium hydroxide powder as the condensing agent, Ohshiro et al. obtained the menthone-isomenthone mixture in moderate yield and in a purity of only 89.8%, whilst in the present process a methoneisomenthone mixture of 98% purity is obtained.

The purity achieved is of particular importance since the greatest part of the menthone-isomenthone mixture is used for the manufacture of menthol, for example by the method of Barney and Hass (Ind. Eng. Chem, 36, (1944)), and the purity requirements of the menthol used for pharmaceutical and cosmetic purposes are extremely high. It is also possible to hydrogenate the piperitenone directly to d,l-menthol. The hydrogenation of the crude piperitenone is carried out in accordance with methods customary for hydrogenations. Amongst the known hydrogenation catalysts, catalysts containing nickel have proved particularly suitable.

It is therefore particularly advantageous if in the hydrogenation of the piperitenone obtained to give the menthol isomer mixture, an unsupported catalyst which essentially contains nickel, or a catalyst which essentially contains nickel on a preferably neutral or weakly basic support, such as a magnesium silicate support, is used. Examples which my be mentioned are Raney nickel and nickel catalysts on silicates, containing magnesium as the support to which optionally small amounts of molybdenum, copper and/or manganese have also been added.

The hydrogenation of the crude piperitenone is expediently carried out at temperatures at which as much d,l-menthol as possible is present in the menthol isomer mixture and no splitting off of water to form pmenthane takes place. Temperatures of l00 to 260C, especially of l 60 to 220C, have proved advantageous.

The hydrogenation can be carried out batchwise or continuously.

To achieve good yields, it is advisable to employ hydrogen pressures of 50 to 300, preferably of I00 to 200, atmospheres gauge.

The reaction time is in general 5 to 30, preferably 12 to 24, hours.

From the mixture of substances formed in the hydrogenation of crude piperitenone it is possible, by frac- Such an isomerization is described, for example, in German Patents 489,819 and 493,268 and in French Patent 1,547,530.

The mesityl oxide used for the examples which follow EXAMPLE 18 was a commercially available product containing 5 200 g of crude piperitenone (piperitenone content: 0.05% of water. 63%) are dissolved in 100 ml of methanol and hydroge- 5 1 EXAMPLE 1 nated with 2 g of Pd/actlve charcoal strength) 11 an excess hydrogen pressure of 200 mm water column. 70 g of methyl vlnyl ketone are added dropwlse ln th initially for 5 hours whilst cooling with ice and then for course of 30 mintucs to 1,000 g of mesityl oxide and 55 48 hours at 25C. The crude product is distilled ml of 30% potassium hydroxide solution whilst stirring through a 1 m packed column. 1 g of a fraction boilat the rellux temperature (approx. 100C). The mixing at 101 to 103l23 mm Hg and consisting of lure is neutralized with glacial acetic acid and the orth e/i m nthone in 98% purity are obtained, ganic phase is distilled. The crude piperitenone (150 g) which passes over after distilling off the mesityl oxide 15 EXAMPLE up to l25/l5 mm Hg contains 68.8% of piperitenone; 1() f 50% ota ium hydroxide solution are the yield of piperitenone is thus 68.8% relative to the dd d i th course f I t 2 minute to a mixture of amount of methyl vinyl ketone employed. 1,500 g of mesityl oxide and 0.5 g of hydroquinone which is boiling at approx. 114C. 83 g of aqueous EXAMPLE 2 methyl vinyl ketone (containing 13 g of water) are then 70 g methyl vinyl ketone are added dropwise in the added dropwise in the course of 60 minutes and at the course of 60 minutes, whilst stirring, to 1,000 g of mesisame time approx. 15 g of water are withdrawn from tyl oxide and 50 ml of 50% potassium hydroxide soluthe condensate of mesityl oxide and water which sepation, at 70C. Thereafter the mixture is stirred for a furrates out at the head of the column and separates into ther 10 minutes at 70C and neutralized with glacial two layers. acetic acid, and the organic phase is distilled. 181 g of The mixture is heated for a further two hours under crude piperitenone are obtained; piperitenone content reflux, and the reaction mixture is neutralized by add- 55.7%, yield therefore 67.2%. ing 8 ml of formic acid and distilled. 156 g of crude pi- The examples which follow were carried out as in Experitenone containing 74% of piperitenone (yield 78%) ample 2 with only the reaction temperature and the are obtained. amount of KOl-l and concentration of KOH being If this crude piperitenone, together with 5 ml of changed in the way indicated. potassium hydroxide solution, is stirred for three hours Example Potassium Hydroxide Solution Temperature Distillate Pipel'itenolle Yield No. Amount Concentration Colltcnt 3 25 ml 50% 50C I52 g 6l.2% 62.0% 4 25 ml 50% C 173 g 57.7% 66.6% 5 25 ml 50% C 183 g 55.3% 67.5% 6 25 ml 50% C 222 g 40.3% 59.7% 7 10 ml 50% 70C 195 g 49.8% 64.7% x 50 ml 50% 70C 181 g 55.7% 67.2 9 m0 ml 50% 70C 180 g 49.5% 59.4% It) 25 ml 30% 70C g 63.87: 57.47: I l 25 ml 40% 70C 147 g 65.9% 64.5% l2 25 ml 60% 70C 210 45.3% 63.5% 13 65 ml 25% reflux I40 g 67.0% 62.7% I4 55 ml 30% reflux 148 g. 63.0% 62.2%

EXAMPLE 15 at 40 50C, the piperitenone content rises to 79%, 70 g of methyl vinyl ketone are added dropwise in the 50 represemmg a total y'eld of plpentenone of course of 60 minutes to 500 g of mesityl oxide and 25 ml of 50% strength potassium hydroxide solution at 70, whilst stirring. Thereafter the mixture is worked up as in Example 2; 125 g of distillate containing 67.8% of piperitenone are obtained; yield 56.6%.

EXAMPLE l6 (comparative example) 70 g of methyl vinyl ketone are added dropwise in the course of 60 minutes at 20C to 1,000 g of mesityl oxide and 20 g of potassium hydroxide powder. 175 g of distillate containing 34.6% of piperitenone are obtained; yield 40.4%.

EXAMPLE l7 70g of methyl vinyl ketone are added dropwise in the course of 60 minutes at 70C to 1,000 g of mesityl oxide and 25 ml of 50% sodium hydroxide solution.

EXAMPLE 20 200 g of crude piperitenone (piperitenone content: 58.7%) are hydrogenated in an autoclave over 5 g of Raney nickel at 200C and atmospheres hydrogen pressure for 24 hours. After filtering off the catalyst, 184 g of a mixture containing 14.2% of neo-menthol, 16.2% of neo-iso-menthol, 14.4% of menthol and 19.4% of iso-menthol remain.

EXAMPLE 21 ing 58.7% of piperitenone is pumped at a speed of ml/hour upwardly through the reactor at 150 atmospheres hydrogen pressure. The table shows the composition of the resulting product as a function of the temperature.

4,165 g of a mixture obtained by hydrogenation of crude piperitenone are distilled through a column of 2 m length and 5 cm diameter, filled with 5 mm wire mesh rings, in a waterpump vacuum, using a reflux ratio of 25 and a through-put of 600 g/hour. The following fractions are obtained:

1. 398 g of by-products (boiling point 50 to 75/20 2. 209 g containing about 50% of neo-menthol and about 50% of by-products (boiling point 75 to 109/20 mm);

3. 1,171 g of a mixture of neo-menthol, neo-isomenthol and menthol (boiling point 109/2O mm);

4. 686 g of menthol (97.7% strength), solidification point (according to German Pharmacopoeia 7) 294C (boiling point 109/20 mm);

5. 551 g of a mixture of menthol and iso-menthol (boiling point 109 to ll0/2O mm).

Renewed distillation of the menthol fraction yields a product of 99.9% purity, solidification point (according to German Pharmacopoeia 7): 3-1 .4C.

We claim:

1. A process for the manufacture of piperitenone by reaction of methyl vinyl ketone with mesityl oxide in the presence of a basic catalyst, in thich methyl vinyl ketone is slowly introduced into a mixture consisting essentially of excess mesityl oxide and, as the catalyst. 40 to 60% w/w aqueous potassium hydroxide solution, the mixture is brought to a temperature of 50 to C, the potassium hydroxide is used in an amount of 0.05 mole to 1.5 mole per mole of methyl vinyl ketone. and the methyl vinyl ketone is introduced into said mixture at said temperature.

2. A process for the manufacture of piperitenone by reaction of methyl vinyl ketone with mesityl oxide in the presence of a basic catalyst, in which methyl vinyl ketone is slowly introduced into a mixture consisting essentially of excess mesityl oxide and, as the catalyst, 20 to 40% w/w aqueous potassium hydroxide solution, the mixture is brought to a temperature of between 80C and the reflux temperature, and the methyl vinyl ketone is introduced into said mixture, and the potassium hydroxide is used in an amount of 0.05 mole to 1.5 mole per mole of methyl vinyl ketone.

3. A process as claimed in claim 1 wherein potassium hydroxide is used in an amount of 0.1 mole to 0.7 mole per mole of methyl vinyl ketone.

4. A process as claimed in claim 1 wherein the resulting crude piperitenone is aftertreated with potassium hydroxide at 20 to 80C for 0.5 to 30 hours.

5. A process as claimed in claim 2 wherein potassium hydroxide is used in an amount of 0.1 mole to 0.7 mole per mole of methyl vinyl ketone.

6. A process as claimed in claim 2 wherein the resulting crude piperitenone is aftertreated with potassium hydroxide at 20 to 80C for 0.5 to 30 hours. 

1. A PROCESS FOR THE MANUFACTURE OF PIPERITENONE BY REACTION OF METHYL VINYL KETONE WITH MESITYL OXIDE IN THE PRESENCE OF A BASIC CATALYST, IN THICH METHYL VINYL KETONE IS SLOWLY INTRODUCED INTO A MIXTURE CONSISTING ESSENTIALLY OF EXCESS MESITYL OXIDE AND, AS THE CATALYST, 40 TO 60% W/W AQUEOUS POTASSIUM HYDROXIDE SOLUTION, THE MIXTURE IS BROUGH TO A TEMPERATURE OF 50* TO 80:C, THE POTASSIUM HYDROXIDE IS USED IN AN AMOUNT OF 0.05 MOLE TO 1.5 MOLE PER MOLE OF METHYL VINYL KETONE, AND THE METHYL VINYL KETONE IS INTRODUCED INTO SAID MIXTURE AT SAID TEMPERATURE.
 1. A process for the manufacture of piperitenone by reaction of methyl vinyl ketone with mesityl oxide in the presence of a basic catalyst, in thich methyl vinyl ketone is slowly introduced into a mixture consisting essentially of excess mesityl oxide and, as the catalyst, 40 to 60% w/w aqueous potassium hydroxide solution, the mixture is brought to a temperature of 50* to 80*C, the potassium hydroxide is used in an amount of 0.05 mole to 1.5 mole per mole of methyl vinyl ketone, and the methyl vinyl ketone is introduced into said mixture at said temperature.
 2. A process for the manufacture of piperitenonE by reaction of methyl vinyl ketone with mesityl oxide in the presence of a basic catalyst, in which methyl vinyl ketone is slowly introduced into a mixture consisting essentially of excess mesityl oxide and, as the catalyst, 20 to 40% w/w aqueous potassium hydroxide solution, the mixture is brought to a temperature of between 80*C and the reflux temperature, and the methyl vinyl ketone is introduced into said mixture, and the potassium hydroxide is used in an amount of 0.05 mole to 1.5 mole per mole of methyl vinyl ketone.
 3. A process as claimed in claim 1 wherein potassium hydroxide is used in an amount of 0.1 mole to 0.7 mole per mole of methyl vinyl ketone.
 4. A process as claimed in claim 1 wherein the resulting crude piperitenone is aftertreated with potassium hydroxide at 20* to 80*C for 0.5 to 30 hours.
 5. A process as claimed in claim 2 wherein potassium hydroxide is used in an amount of 0.1 mole to 0.7 mole per mole of methyl vinyl ketone. 